Obesity is a major nutritional disorder in industrialized and developing countries. The prevalence of obesity and frequently associated type 2 diabetes is rapidly increasing. Back in 1994, it was predicted that there would be 239 million people with diabetes in 2010. In 2007, however, there are already 246 millions diabetic people around the world [Diabetes Atlas 2006; http://www.eatlas.idf.org]. Much of this is driven by the obesity epidemics. WHO (World Health Organization, http://www.who.int) estimates that there are 1.6 billion adults (older than 15) who are overweight and 400 million adults who are obese. This is double of the estimations made in 1995. These numbers increase each year.
Obesity is characterized by accumulation of body fat mass resulting from a positive imbalance between energy intake and energy expenditure. This accumulation of body fat is due to an excess of adipose tissue containing adipocytes, most predominately under the skin, in the abdominal cavity, round the blood vessels, and in mammary gland. A body mass index (BMI=body weight (kg)/height (m)2) above 30 kg/m2 defines obesity.
Obesity is associated with a myriad of complications and an increased risk for type 2 diabetes, dyslipidemia, hypertension, cardiovascular diseases, stroke, hepatic diseases, some cancer, sleep apnea, bone osteoarthritis, infertility, gallstones etc. Particularly, obesity often involves pathologies or disorders associated with deregulation of glucose homeostasis, such as insulin resistance, glucose tolerance and type 2 diabetes.
Type 2 diabetes, also called maturity-onset diabetes mellitus or non-insulin-dependent diabetes mellitus, usually develops rather gradually after the age of 40. However, the number of children and adolescents with type 2 diabetes is increasing at a worrying rate, in parallel with the rise of the incidence of overweight and obesity in the youths.
Type 2 diabetes is a consequence of deregulation of glycemia, which is too elevated. The proper level of blood glucose, or glycemia, is maintained by several hormones. The most important are glucagon, which is a hyperglycemic hormone and insulin, which is the unique hypoglycemic hormone.
The polypeptide hormone insulin acts mainly on muscle, liver, and adipose tissue cells to stimulate the synthesis of glycogen, triglycerides and proteins while inhibiting the breakdown of metabolic fuels, such as triglycerides. In addition, insulin stimulates the uptake of glucose by most cells, with the exception of brain and liver cells. Type 2 diabetic individuals have elevated plasma glucose and insulin levels. This results from resistance to the hypoglycaemic action of insulin in various tissues and organs. The molecular mechanisms of insulin resistance involve post-receptor alteration of signalling in insulin target cells, such as muscle cells. Concomitantly, progressive insulin secretory defect arises due to pancreatic β-cells exhaustion. These dual defects combined lead to reduced glucose tolerance, increased fasting glucose and, eventually, to overt type 2 diabetes (1).
Type 2 diabetes causes various disabling microvascular complications in patients. Besides retinopathy, nephropathy, neuropathy, erectile dysfunction, the disease is also associated with accelerated atherosclerosis and premature cardiovascular morbidity and mortality. Cardiovascular disease accounts for up to 60% of all deaths from diabetes and is the most common complication in Europeans with type 2 diabetes (2); those who are obese in middle age have twice to quadruple risk of being hospitalized for coronary heart disease in old age (3). Indeed, increased incidence of atherosclerosis, myocardial infarction, stroke, and peripheral vascular disease is intricately associated with insulin resistance, which is a major pathophysiologic abnormality in type 2 diabetes. Careful control of glycaemia is needed to reduce the risk of long term complications. This is theoretically achievable with combinations of diet, exercise and weight loss, various oral antidiabetic drugs (metformin, sulfonylureas, glitazones, acarbose), and insulin use for type 2 patients not responding to oral medications (4).
In the field of antidiabetic treatments, however, nearly half of the patients do not achieve their glycaemia target and most therapies (like sulfonylureas and insulin) lead to weight gain (5-7). Thus, there is still a real need for new drugs for preventing and treating this obesity-associated disorder. Preventing or delaying glycaemia deregulation in the early phases of type-2 diabetes could help to reduce the prevalence of this severe and life threatening complication of obesity.
Cathepsins are lysosomal cysteine proteases that belong to the papain superfamily. They are widely distributed and differentially expressed among tissues. These enzymes have a role in processes that involve proteolysis and turnover of specific proteins and tissues. Cathepsins also participate to proenzyme activation and to antigen presentation by MHC class 2 proteins in antigen-presenting cells. The various members of this family are differentially expressed, and some forms of cathepsins are closely associated with monocytes, macrophages, and other cells of the immune system. The secreted forms of several members of this family function in tissue remodelling through degradation of collagen, fibronectin, laminin, elastin, and other structural proteins and are implicated in inflammation associated with immunological response and in metastasis (8). Some cathepsins have been specifically implicated in obesity and related complications. The circulating concentrations of Cathepsin L and S are increased with obesity and type 2 diabetes (9; 10). Cathepsin S is expressed and secreted by human adipose tissue cells, in increasing amounts in response to inflammatory factors (9). Moreover, Cathepsins S, L and K interfere with adipogenesis in vitro and with fat mass accretion in mice (10-12). Cathepsin L has been proposed to be a target for treatment and diagnosis of obesity and diabetes (WO02064613). Cathepsin K and Cathepsin B inhibition are also proposed for the treatment of obesity (CA2561032, WO05097103, WO06076796).